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ABSTRACT
The transition from rolling to firm adhesion is a key element of neutrophil activation and essential to the inflammatory response. Although the molecular mediators of rolling and firm adhesion are known to be selectins and β^sub 2^-integrins, respectively, the precise dynamic mechanism by which these ligands facilitate neutrophil arrest remains unknown. Recently, it has been shown that ligation of E-selectin can stimulate the firm adhesion of neutrophils via a MAP-kinase cascade. To study the possible mechanism by which neutrophil arrest could occur, we created an integrated model by combining two methodologies from computational biology: a mechanics-based modeling of leukocyte adhesion (adhesive dynamics) and signal transduction pathway modeling. Within adhesive dynamics, a computational method our group has shown to accurately recreate rolling dynamics, we include a generic, tunable integrin activation module that links selectin engagement to integrin and activity. This model allows us to relate properties of the activation function to the dynamics of rolling and the time and distance rolled before arrest. This integrated model allows us to understand how intracellular signaling activity can set the timescale of neutrophil activation, adhesion, and diapedesis.
INTRODUCTION
For a neutrophil to perform its phagocytic function in the tissue, it must exit the bloodstream. In response to inflammatory chemokines, endothelial cells in venules upregulate and present E- and P-selectin on their luminal surfaces. Leukocytes expressing the selectins' glycosylated ligands transit though the vasculature and interact with the endothelium through transient receptor-ligand bonding, a behavior otherwise known as rolling. Selectin-mediated rolling is followed by integrin-mediated firm adhesion and subsequent leukocyte extravasation and chemotaxis to the site of tissue injury.
The transition from rolling to firm adhesion results from β^sub 2^-integrin activation, during which a conformational change in the integrin improves its affinity for intercellular adhesion molecule-1 (ICAM-1), its endothelial ligand. The structure of the resting integrin resembles a folded switch-blade, such that upon activation, the α and β cytoplasmic domains separate, and the protein swings open into an extended conformation, freeing the N-terminal headpiece from the C-terminal, membrane-proximal domain (1,2). Studies of rolling in cells transfected with wild-type, locked-open (extended), and locked-closed conformations of leukocyte function-associated antigen-1 (LFA-1) showed that the conformational presentation of I-domain, the ICAM-binding region in the integrin headpiece, indeed regulates the transition from rolling...